PROJECT SUMMARY Amyloid-beta (A?) has been shown to be critical in the pathophysiology of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) A? and amyloid plaque emission tomography (PET) tracers are established biomarker for detecting amyloid plaques in the brain. Current screening for clinical trials, especially prevention trials, are hampered by complex, expensive or invasive procedures, with limited availability. Our overall goal is to determine the relationship between blood plasma A? and the presence of amyloid plaques in the human brain to improve screening for AD and to validate an AD blood test. The relationship and timing of blood A? changes relative to amyloid PET measures of plaques and CSF A? are not understood. There are several questions that have not been addressed before: ?Does blood A? change before, at the same time or after changes in CSF or amyloid PET?', `What demographic, clinical, or genetic factors influence plasma A???. We hypothesize that abnormal plasma A? is predictive of abnormal CSF A? and amyloid PET. In Aim 1, we will leverage existing plasma and CSF samples from regional, national and international studies to test our hypothesis in well- characterized research cohorts. We will use longitudinal samples to investigate the temporal sequence of changes of plasma A?, CSF A?, and amyloid PET to understand at which stage of AD plasma A? becomes abnormal. We will also look at several cofactors to determine their impact on plasma A? measures of brain amyloid plaques, including age and APOE ?4. In Aim 2, we will implement a prospective, population based, blood A? test to screen individuals for amyloidosis with confirmation using amyloid PET. Based on the results of the blood amyloid test, a subset of participants will follow-up with confirmatory amyloid PET and repeat blood collection and tests. This will allow us to compare the blood A? test to the current gold standard of amyloid PET scans. The proposed work builds on the prior pioneering approach that has influenced the understanding of the role of A? in the amyloid hypothesis and pathophysiological causes of AD. We have extended this approach with significantly improved techniques, discovery of a blood A? signature of amyloid plaques, and now seek to validate the test in a real-world prospective study with a population-based cohort. These studies will lay the groundwork for rapid deployment to accelerate enrollment of AD trials and clinical diagnosis.